One other feature of the structural organization of the liver bears emphasis because of its clinical significance. Branches of the hepatic vein, hepatic artery, and bile ducts run in parallel in the so-called hepatic triad. Hepatocytes lying closest to this triad are referred to as periportal, or zone 1, and have the greatest supply of oxygen and nutrients. In contrast, hepatocytes lying closest to branches of the hepatic vein are referred to as pericentral, or zone 3. The latter cells are more sensitive to ischemia, whereas the former are more sensitive to oxidative injury. Thus the location of damaged cells on biopsy may provide clues to the cause of a given case of liver injury. Zone 1 cells are most active in detoxification functions in normal circumstances, but •Fig. 32.4 Functionalanatomyofthebiliarysystem.Right and left hepatic ducts from liver Common hepatic duct Common bile duct Cystic duct Sphincter of Oddi Duodenum Gallbladder zone 2 (intermediate between zones 1 and 3) and zone 3 cells can progressively be recruited in cases of liver disease. Conversely, zone 3 cells are thought to be most active in bile acid synthesis.
Bile is the excretory fluid of the liver that plays an important role in lipid digestion. Bile formation begins in hepatocytes, which actively transport solutes into bile canaliculi across their apical membranes. Bile is a micellar solution in which the major solutes are bile acids, phosphatidylcholine, and cholesterol in an approximate ratio of 10:3:1, respectively. Secretion of these solutes drives concomitant movement of water and electrolytes across the tight junctions that link adjacent hepatocytes to form canalicular bile. The majority of bile flow is driven by the secretion of bile acids across the apical membrane of hepatocytes via an adenosine triphosphatase (ATPase) transporter known as the bile salt export pump (BSEP; see
Table 32.1 ). The composition of the resulting fluid can be modified further as it flows through the biliary ductules (resulting in hepatic bile) and still further on storage in the gallbladder (gallbladder bile). Ultimately bile becomes a concentrated solution of biological detergents that aids in solubilization of the products of lipid digestion in the aqueous environment of the intestinal lumen, thereby enhancing the rate at which lipids are transferred to the absorptive epithelial surface. It also serves as a medium in which metabolic waste products are exported from the body.
Thoughrare,avarietyoffamilialsyndromesthataremanifestedasprogressivecholestasishavetaughtusagreatdealaboutthemolecularnatureofthetransportersthatdeliverbileconstituentsintothecanaliculus.Forexample, (PFICII)hasbeenmappedtoamutationinBSEP thatresultsinanalmosttotalabsenceofbileacidsinbile.Cholestasisdevelopsinpatientswiththisdisorder,buttheyhaverelativelylittleifanyevidenceofbileductinjury.TypeIIIPFIContheotherhandisamuchmoreaggressivediseaseinwhichcholestasisisaccompaniedbyearlyincreasesincirculatingγ-glutamyltranspeptidase.Themolecularculpritisamutationthatabolishesexpressionofmultidrug resistance protein 3 (MDR3).Intheabsenceofthistransporter,phosphatidylcholineisnolongerabletoenterbile,thusillustratingtheimportanceofthislipidinprotectingcholangiocytesfromtheinjuriouseffectsofbileacids,becausemixedmicellescannotforminitsabsence.
Bile acids are produced by hepatocytes as end products of cholesterol metabolism. Cholesterol is selectively metabolized by a series of enzymes that result in formation of bile acid (